USP <797> Pharmaceutical Compounding - Sterile

Preparations Proposed Revision: Understanding the Impact to Home

Infusion

Connie Sullivan, BSPharm Vice President of Research and Innovation

Disclaimer

Connie Sullivan is presenting this information solely as a representative of NHIA and is not speaking on behalf

of USP or the USP Compounding Expert Committee

Objectives By the end of this presentation you should be able to:

1.  Identify the proposed changes to USP Chapter <797> that will most impact home infusion providers.

2.  Understand how to provide comments to USP regarding the proposed revision to Chapter <797>.

What Didn’t Change

•  Shift from low, medium, and high risk to Category 1 and Category 2 classification system

•  References to USP <800> for hazardous drugs

•  Improved organization and flow •  Procedure boxes

Summary of Major Changes

•  Revised Introduction and Scope sections describing when to apply the chapter

•  Elimination of “urgent-use” exemption •  Elimination of “in-use” time terminology •  Changes to required frequencies for personnel

qualifications and environmental monitoring •  New section specific to allergen extracts •  Removal of radiopharmaceuticals to a separate

chapter

Scope of USP <797>

•  Definition of compounding •  Combining, admixing, diluting, pooling,

reconstituting, repackaging, altering1 •  Definition of administration

•  Direct and immediate application by injecting, infusing, or otherwise providing a sterile medication in its final form1

•  Remains outside the scope of <797>

Administration •  New “immediate-use” provision exempts preparation

of a conventionally manufactured, non-hazardous, CSP for a single patient when:

1.  Prepared in accordance with the directions in the approved labeling

2.  Administration starts within one hour of beginning preparation

3.  Administration “should” follow the manufacturer or compounders labeling, and “must” follow applicable laws

4.  Aseptic technique must be used 5.  Discard unused starting ingredients unless labeled

as a multiple-dose container

Scope of USP <797>

•  Broader list of practitioners & settings including, but not limited to:

•  Pharmacists •  Technicians •  Nurses •  Physicians

•  Veterinarians •  Naturopaths •  Chiropractors •  Dentists

CSP Categories

Two categories of CSPs: – Category 1 – Category 2

•  Distinguished by environment in which they are made, probability for microbial growth, and time within which they will be used.

Category 1 CSPs •  Maximum BUD of 12 hours RT, 24

hours REF •  Primary Engineering Control (PEC) not

required to be located in a classified area

Category 2 CSPs •  BUD > 12 hour RT, > 24 hour REF •  PEC located in ISO 7 (or better) •  Sterility testing required depending on

assigned BUD o  Endotoxin testing if using non-sterile

sources o  See Table 12 in the proposed revision

Personnel Qualification Current

Standard 2015

Proposed Revision

2018 Proposed Revision

Visual observation of hand hygiene and garbing

Annual Quarterly 6 Months

Gloved fingertip and thumb testing

Annual* Quarterly 6 Months

Media fill Annual* Quarterly 6 Months

*For low and medium risk compounding

Personnel Qualification • More prescriptive minimum requirements for documenting media fill competency

• Calculations included in minimum principle proficiencies

• Competencies must be complete before an employee can compound “independently”

• Initial gloved fingertip testing 3x, in buffer room or SCA, subsequent in PEC after media fill

• Failures in competency testing require a single successful re-test

• Requalification after a gap in compounding extended to 6 months from 3 in prior proposed revision

Garbing •  No electronic devices (headphones, cell

phones) not required for compounding •  Requirement for sterile gown or sterile

sleeves is removed •  Garb cannot be re-used once you exit the

cleanroom •  Garbing order is based on facility SOP

Facility Requirements •  Humidity below 60% •  Temperature 20 degrees or cooler •  Physically separate “rooms” vs. “areas” •  Introduction of cleanroom “suite” terminology •  HEPA filter placement for both ante and

buffer room must be in the ceiling •  Returns low on walls unless otherwise

verified by a smoke study •  Minimum requirement of 20 ACPH in the ISO

8 area

Facility Requirements •  “Should” minimize dust collecting overhangs,

“must” be easily cleaned •  Pass-through doors “should” be interlocking •  No tacky mats in classified areas •  Access doors “should” be hands-free •  Smoke studies “must” demonstrate proper

placement of PEC and compounder ability to maintain first air in the direct compounding area

RABS and Isolators

•  RABS – must be placed in an ISO 7 area with cleanroom suite configuration for compounding Category 2 CSPs

•  Isolators must be placed in ISO 8 air quality to compound Category 2 CSPs

•  Placement confirmed by smoke pattern visualization test every 6 months

Certification and Recertification

•  Certification requirements apply to classified areas and PEC

•  Nonviable air is included in certification section vs. EM

•  Frequency remains initial and every 6 months

•  Suggested corrective actions for nonviable when action levels are exceeded

Microbiological Air and Surface Monitoring

•  New terminology for viable air sampling •  Frequencies changed from 2015 proposed

revision

Current 2015 Proposed Revision

2018 Proposed Revision

Viable Air 6 Months Monthly 6 Months

Surface Risk based Monthly Monthly

Action Level Guidance •  Viable air sample action levels revert to

current standard •  Surface sampling action levels condensed

vs. varied by work surface or non-work surface as proposed in prior draft

•  Surface action levels for ISO 8 or worse changed to >50 cfu/device or swab

•  Modified incubation procedures •  Recover to genus level for excursions, “with

assistance of a microbiologist”

Cleaning and Disinfecting •  Performed by trained, garbed personnel •  Sporicidal frequency reduced to monthly

from weekly in prior proposed revision (currently not required)

•  New table for cleaning frequencies is more specific and user friendly

•  Requirement for sterile cleaning tools removed

•  No corrugated cardboard in classified areas

Master Formulation Records Required when:

– Preparing batches for multiple patients – Compounding from non-sterile ingredients

Master Formulation Record Must include:

–  Name, strength or activity, dosage form of CSP –  Identities and amounts of all ingredients –  Type and size of container systems –  Physical description of final preparation –  Complete instructions including equipment,

supplies and compounding steps –  BUD and storage requirements –  Reference to support stability

Compounding Records •  Required for all CSPs •  Identity of all individuals involved in the

preparation of the CSP •  Provide traceability of all ingredients •  Cross-reference this requirement with

Section 15.1 (line 1783)

Labels Current 2018 Proposed Revision

Ingredient name Active ingredients and amounts, activities or concentrations

Amount or concentrations of ingredients

Volume if not obvious from the container

Volume Route of admin if not obvious

Route of administration BUD

BUD Storage conditions if other than RT

Storage conditions Date Prepared

Statement of compounding

Contact information of compounding facility

Special handling or warnings

If the CSP is multi-dose

Beyond Use Dates (BUDs)

•  Category 1: Limited to 12 hrs or less RT, 24 hrs or less REF

•  Category 2: Depending on the following: –  Method of preparation

•  Aseptic or terminal sterilization –  Sterility of starting components –  Sterility testing performed –  Presence of preservatives –  Storage conditions

Summary of Category 2 BUD Changes

*Low risk CSPs are 48 hours RT and 14 days REF, medium risk CSPs are 30 hours RT and 9 days REF. **Assumes no preservative present for comparison to the 2015 proposed revision BUDs.

Release Testing •  No requirement to visually inspect against a lighted

white background and a black background for particulates

•  If a CSP is assigned a BUD that requires sterility testing, then Sterility Testing <71> applies

•  Exception for batch sizes of 1-39 units •  Batch sizes of 40+ must use Chapter <71> Table 3

•  CSPs may be dispensed before the end of the sterility testing period if (prescriber specifically requests dispensing prior to known sterility results) the facility has procedures to:

1.  Notify prescriber of a testing failure 2.  Determine whether a recall is necessary *Above requirements are moved to Section 15. Quality Assurance and Control

Changes to In-Use Times Section

•  Broken into two new sections based on whether the component is a conventionally manufactured product or a CSP

•  Section 13. Use of Conventionally Manufactured Products

•  Section 14. Use of CPSs as Components

Quality Assurance and SOPs •  Much of the detail is removed from

these sections •  Refers to <1163> Quality Assurance in

Pharmaceutical Compounding •  Note references to a “designated

person” throughout the chapter

Allergenic Extracts New Section 18 applies when:

1.  Simple transfers of conventionally manufactured, sterile components

2.  Manipulations are limited to penetrating disinfected stoppers to transfer sterile liquids

3.  Use sterile syringes and needles to perform compounding

Summary of CSP Compounding Requirements and BUDs in the 2018 Proposed Revision

*A PEC is optional for allergenic extracts

Timeline for Submitting Comments

•  Official publication in Pharmacopeial Forum (PF) is September 4, 2018

•  USP Open Mic Session – September 5, 2018 •  Comment period closes November 30, 2018

•  Submit comments to USP http://www.usp.org/compounding/general-chapter-797

•  Email to connie.sullivan@nhia.org •  Final publication – June 1, 2019 •  Effective date – Dec. 1, 2019

References 1. USP. Proposed revisions to Chapter <797>, July 2018. Available at: http://www.usp.org/compounding/general-chapter-797 (accessed July 27, 2018) 2. United States Pharmacopeial Convention, Inc. Chapter <797>. United States Pharmacopeia 39 –National Formulary 34. Rockville, MD: United States Pharmacopeial Convention, Inc.; 2016. 3. USP. Proposed revisions to Chapter <797>, September 2015. Available at: www.usp.org/sites/default/files/ usp_pdf/EN/USPNF/usp-gc-

Questions?